Letter pubs.acs.org/macroletters
Zwitterionic Ring Opening Polymerization with Isothioureas Xiangyi Zhang and Robert M. Waymouth* Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States S Supporting Information *
ABSTRACT: Bicyclic isothioureas 1 and 2 mediate controlled ring opening polymerizations (ROP) of lactides in the absence of protic initiators to afford high molecular weight polylactides (PLA) with narrow polydispersities. The cyclic structure of the resulting PLA was determined by dilute solution viscosity measurement and MALDI-TOF mass spectrometry. Compared to DBU initiator, isothioureas are more selective for producing cyclic PLA without appreciable linear contaminants. Mechanistic studies involving acyl amidinium support our hypothesis that DBU-initiated ZROP generates linear chains from a ketene aminal intermediate.
Z
molecular weight PLAs with Mn ranging from 38000 to 66000 Da and polydispersities of Mw/Mn = 1.3−1.7 were produced at high conversion (∼90%). The polymerization rates with isothioureas are significantly slower than those with DBU or NHCs. Kinetic studies (Figures S6 and S7, Supporting Information) indicate that this is likely due to the lower initiation efficiency for the ITU nucleophiles relative to DBU.27,28 The molecular weights of the PLAs generated from ITU 1 were lower than those from ITU 2 or DBU. The evolution of molecular weight (Mn) exhibits a linear correlation with monomer conversion (c), but extrapolation of Mn versus conversion plot to zero conversion does not go through the origin (Figure S2, Supporting Information). The molecular weights do not correlate to the initial monomer/initiator ratio [M]0/[I]0 and are significantly higher than the simple prediction based on c·[M]0/[I]0. Similar behavior was observed for the zwitterionic ring-opening polymerization of lactones1,16,20−22 and is attributed to a slow rate of initiation relative to propagation.20,22 This is also evident in the kinetic behavior, where an induction period is observed followed by a first order disappearance of monomer (Figures S6 and S7, Supporting Information). The cyclic structure of the PLA generated from isothioureas 1 and 2 was inferred by a combination of 1H NMR spectroscopy, MALDI-TOF mass spectrometry, and dilute solution viscosity measurements. The 1H NMR spectra of the PLA shows no observable end groups (Figure S1). A MALDITOF mass spectrum of a crude polymer sample obtained by quenching the reaction at low conversion (8%) with 4nitrophenol shows molecular ions assigned as the sodium adducts of cyclic PLA (Figure 1). The inset of the figure presents a detailed picture of mass range from 4700 to 5300 and reveals two different populations of macromolecules separated by 72 mass units, which corresponds to the even-
witterionic ring opening polymerization (ZROP) mediated by organic nucleophiles has been developed as an effective strategy for the synthesis of cyclic polymers.1−7 In the absence of protic initiators, nucleophiles such as N-heterocyclic carbenes,1,6 pyridines,8,9 imidazoles,10 amidines,11 tertiary amines,8,12,13 or phosphines9 can mediate the ring opening of strained cyclic monomers to form zwitterionic intermediates14,15 that propagate and cyclize to release macrocycles (Scheme 1). Lactones,1,2,16 thiolactones,8 N-carboxyanhydrides,6,17,18 or carbosiloxanes19 are among the types of monomers that can be polymerized with this approach, but the factors that control the rate of initiation, propagation, and cyclization and competitive side reactions remain incompletely understood and depend sensitively on the reactivities of nucleophilic initiator, the monomer, the nature of the reactive intermediates, and the polymerization conditions.1,4,20,21 The ZROP of lactide with N-heterocyclic carbenes is rapid (minutes), but molecular weights >30 kDa are difficult to obtain.16,22,23 We recently reported that the amidine 1,8diazabicyclo-[5.4.0]undec-7-ene (DBU) was sufficiently nucleophilic to mediate the ZROP of lactide to generate cyclic polylactides but was accompanied by the cogeneration of linear polylactides.11 We had proposed that the linear polylactides might arise from competitive deprotonation of the amidininium zwitterion to generate the neutral ketene aminal (KA, Scheme 2).11 To test this hypothesis and to provide a strategy for eliminating this competitive pathway, we investigated the ZROP of lactide with the isothioureas24−26 1 and 2. While the isothioureas are less nucleophilic than the amidine DBU,27,28 we reasoned that the acylated isothiourea zwitterions would be unable to deprotonate to the ketene aminal and, thus, be less likely to generate linear chains. Herein, we employ ITU 1 and 2 as nucleophilic initiators for the ZROP of LA and compare the results with the DBU initiator. The ROP of L-lactide in the absence of added alcohol initiators was carried out in dichloromethane at room temperature with ITU 1 or 2 as catalysts (Table 1). High © 2014 American Chemical Society
Received: August 25, 2014 Accepted: September 19, 2014 Published: September 23, 2014 1024
dx.doi.org/10.1021/mz500525n | ACS Macro Lett. 2014, 3, 1024−1028
ACS Macro Letters
Letter
Scheme 1. Nucleophilic Zwitterionic Ring-Opening Polymerization for the Synthesis of Cyclic Polymers
Scheme 2. Proposed Reaction Pathway for DBU-Initiated ROP of LA
Table 1. ROP of LA by Isothioureas or DBU Catalysts in the Absence of Alcohol entry
initiator
[LA]0 (mol/L)
[LA]0/[I]0
time (h)
% conv.a
Mnb (Da)
PDIb
Mwc
ηx/ηlineard
1 2 3 4 5
ITU 1 ITU 1 ITU 2 ITU 2 DBU
2.0 2.0 2.0 2.0 1.0
20 10 20 10 100
42 23 135 93 1
94 95 86 89 89
48000 38000 66000 53000 58000
1.39 1.42 1.65 1.53 1.59
44000 36000 82000 67000 78000
0.68 0.68 0.67 0.68 0.84
a Conversion determined by 1H NMR. bMn and PDI determined by PS calibrated GPC in THF. cAbsolute molecular weight determined by GPC using multiangle light scattering (MALS). dRatio of intrinsic viscosity of PLA generated with nucleophiles relative to a linear PLA generated by TBD in the presence of alcohol initiators, determined by GPC with in-line viscometer and right angle light scattering.
consistent with a zwitterionic polymerization mechanism where the initiation step involves the nucleophilic addition25 of the isothiourea to lactide to generate a zwitterionic intermediate. This intermediate can either cyclize to regenerate lactide or the neutral tricycle11,30 (likely a dormant species) or add additional monomer to propagate to larger zwitterions. The induction period observed in the kinetic behavior suggests that this initiation step is kinetically inefficient, either due to an unfavorable equilibrium constant (k1/k−1) for initiation or to a buildup of the dormant tricycle T1 (Scheme 3). Cyclization of the growing zwitterions by either “backbiting” into internal esters of the growing zwitterions (path b) or at the isothiouronium terminus (path a) would liberate cyclic chains. The moderate increase in polydispersity with conversion indicates the possibility of chain transfer reactions such as the attack of active zwitterions on the internal esters of other zwitterions as well as cyclized chains, which has been previously proposed as the key step for the generation of high molecular weight cyclic polycaprolactone.20
and odd-numbered lactic acid repeat units in the cyclic polymers. That the ions corresponding to odd-numbered lactide units are of much lower intensity than the even-numbered ones indicated that cyclic PLAs are mainly formed via closing the two chain ends without notable backbiting or chain scrambling, at least at these low conversions. Further evidence for the cyclic structure of these PLAs was provided by the comparisons of the intrinsic viscosity of the PLAs generated from isothioureas 1 and 2 relative to a linear sample of similar molecular weight. The ratio of intrinsic viscosities [η]isothiourea/[η]linear = 0.68 (Figure S3, Supporting Information) is similar to that predicted (0.667) for a cyclic polymer in a theta solvent.29 In contrast, a ratio of [η]DBU/[η]linear = 0.84 was observed for the PLA generated from DBU, consistent with a mixture of cyclic and linear chains in the latter case. These data indicate the isothioureas 1 and 2 exhibit a higher selectivity than DBU for forming cyclic chains. The ring-opening polymerization of lactide with the isothioureas 1 and 2 in the absence of alcohol initiators is 1025
dx.doi.org/10.1021/mz500525n | ACS Macro Lett. 2014, 3, 1024−1028
ACS Macro Letters
Letter
Figure 1. MALDI-TOF MS spectrum of a low molecular weight PLA generated by ITU 2.
chains, respectively. Treatment of a toluene solution of isothioureas 1 or 2 with benzoyl chloride resulted in the precipitation of the acylated isothioureas 3 and 4 (Scheme 4a), which were isolated in 99% yield and characterized by 1H and 13 C NMR and high-resolution mass spectrometry (Supporting Information). Treatment of 3 or 4 with 1.2 equiv of sodium methoxide in CDCl3 at room temperature proceeded rapidly (80−90% in 30 min) to give methyl benzoate and free isothiourea. These results provide good chemical evidence for the cyclization step at the acyl isothiouronium terminus of the zwitterion (path a, Scheme 3). In contrast, the acylated isothioureas 3 and 4 are less reactive with methanol: 3 or 4 did not react readily with a stoichiometric amount of methanol in CDCl3 at room temperature. However, stirring 3 or 4 in methanol for 6 h at room temperature liberated methyl benzoate and the protonated isothioureas. This observation is consistent with the generation of linear chains upon methanolic workup of the reaction; any macrozwitterions that have not yet cyclized should react with wet methanol to generate linear chains with methanol or water end groups (Scheme 3), as observed in the MALDI-TOF mass spectrum of the sample isolated after dialysis of the crude polymer sample in methanol overnight (Figure S4). To contrast the behavior of the isothioureas to that of DBU, we also carried out analogous studies with the amidine. Treatment of a toluene solution of DBU with benzoyl chloride generated the acylated DBU 5 along with a significant amount of ketene aminal 6 and protonated DBU 7 as the side products (Scheme 4b). The ratio of 5 to 6 depends on the relative amount of DBU to benzoyl chloride and the order of addition, but we were unable to identify conditions that would lead to 5 as the sole product, which suggests that the rate of deprotonation of 5 by DBU is competitive to the rate of formation of 5 from DBU and benzoyl chloride. The ketene aminal 6 was not stable under ambient conditions and quickly hydrolyzed to amide 8 during isolation.
Scheme 3. Proposed Mechanism for ZROP of Lactide with Isothioureas
The observation that even-numbered cyclic poly(lactides) predominate at low conversions suggest that cyclization at the isothiouronium terminus (path a) is preferred, at least for modest molecular weights (Mn ≤ 9000 Da). That methanol and water terminated linear chains are observed in the MALDI mass spectra for polymer samples quenched at low conversions (∼8%) and worked up in wet methanol (Figure S4, Supporting Information) is consistent with the methanolysis/hydrolysis of active zwitterions that have not cyclized.20 Mechanistic studies were carried out to investigate the reactivity of the acylated isothioureas to provide independent evidence that the attack on acylisothiouroniums (the positive terminus of a zwitterion) by either the alkoxide chain end or methanol solvent (work up) would generate cyclic or linear 1026
dx.doi.org/10.1021/mz500525n | ACS Macro Lett. 2014, 3, 1024−1028
ACS Macro Letters
Letter
Scheme 4. Synthesis and Reactivity of Acylisothiouronium (a) and Acylamidinium (b)
■
Similar observations were made by Quaranta in reactions of DBU with alkyl carbonates.31 These model studies provide evidence for the competitive formation of ketene aminals during the ZROP of lactones by DBU.20 In addition, the different reactivity of the acylated isothioureas and acylated amidines reflect the higher selectivity of the isothioureas in generating cyclic macromolecules. In summary, the bicyclic isothioureas 1 and 2 are competent nucleophilic initiators for the zwitterionic ring-opening polymerization of lactide to generate macrocyclic polylactides with Mn = 38000−66000 Da. In the absence of protic initiators, the ZROP of lactide mediated by isothioureas 1 and 2 generate high molecular weight cyclic PLA under conditions where the amidine DBU generates mixtures of cyclic and linear chains. Mechanistic studies reveal that the acylated amidines are readily deprotonated to the ketene aminal, whereas the acylated isothioureas are not. These experimental results support our hypothesis that linear chains in the DBU-mediated ZROP of lactide comes from a ketene aminal intermediate. Isothiourea catalysts that effectively eliminate this unwanted pathway are more selective for the formation of cyclic PLA. In addition, the observation that both amidines and isothioureas can mediate the nucleophilic zwitterionic ringopening reactions implies that attempts to generate high molecular weight linear polymers (i.e., at high monomer/ alcohol initiator ratio) utilizing thiourea/DBU or isothiourea cocatalyst systems32−34 are likely to be compromised by the competitive zwitterionic ring-opening polymerization mediated by the amidine as a nucleophile.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This material is based on work supported by the National Science Foundation (DMR-1407658 and GOALI CHE1306730).
■
REFERENCES
(1) Brown, H. A.; Waymouth, R. M. Acc. Chem. Res. 2013, 46, 2585− 2596. (2) Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.; Waymouth, R. M. Macromolecules 2010, 43, 2093−2107. (3) Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. Chem. Rev. 2007, 107, 5813−5840. (4) Kricheldorf, H. R. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 251−284. (5) Laurent, B. A.; Grayson, S. M. Chem. Soc. Rev. 2009, 38, 2202− 2213. (6) Guo, L.; Lahasky, S. H.; Ghale, K.; Zhang, D. H. J. Am. Chem. Soc. 2012, 134, 9163−9171. (7) Jia, Z. F.; Monteiro, M. J. J. Polym. Chem., Part A: Polym. Chem. 2012, 50, 2085−2097. (8) Kricheldorf, H. R.; Lomadze, N.; Schwarz, G. Macromolecules 2007, 40, 4859−4864. (9) Piedra-Arroni, E.; Ladavière, C.; Amgoune, A.; Bourissou, D. J. Am. Chem. Soc. 2013, 135, 13306−13309. (10) Kricheldorf, H. R.; Lomadze, N.; Schwarz, G. Macromolecules 2008, 41, 7812−7816. (11) Brown, H. A.; De Crisci, A. G.; Hedrick, J. L.; Waymouth, R. M. ACS Macro Lett. 2012, 1, 1113−1115. (12) Kricheldorf, H. R.; Garaleh, M.; Schwarz, G. J. Macromol. Sci., Part A: Pure Appl. Chem. 2005, 42, 139−148. (13) Coulembier, O.; De Winter, J.; Josse, T.; Mespouille, L.; Gerbaux, P.; Dubois, P. Polym. Chem. 2014, 5, 2103−2108. (14) Johnston, D. S. Adv. Polym. Sci. 1982, 42, 51−106.
ASSOCIATED CONTENT
S Supporting Information *
Experimental details, synthetic procedures, and characterization data (NMR data and MALDI mass spectra). This material is available free of charge via the Internet at http://pubs.acs.org. 1027
dx.doi.org/10.1021/mz500525n | ACS Macro Lett. 2014, 3, 1024−1028
ACS Macro Letters
Letter
(15) Suzuki, M. In Encyclopedia of Polymer Science and Technology, 4th ed.; John Wiley & Sons, Inc.: New York, 2013. (16) Culkin, D.; Jeong, W.; Csihony, S.; Gomez, E.; Balsara, N.; Hedrick, J. L.; Waymouth, R. Angew. Chem. 2007, 119, 2681−2684. (17) Kricheldorf, H. R.; Von Lossow, C.; Schwarz, G. J. Polym. Chem., Part A: Polym. Chem. 2006, 44, 4680−4695. (18) Guo, L.; Zhang, D. J. Am. Chem. Soc. 2009, 131, 18072−18074. (19) Brown, H. A.; Chang, Y. A.; Waymouth, R. M. J. Am. Chem. Soc. 2013, 135, 18738−18741. (20) Brown, H. A.; Xiong, S. L.; Medvedev, G. A.; Chang, Y. A.; AbuOmar, M. M.; Caruthers, J. M.; Waymouth, R. M. Macromolecules 2014, 47, 2955−2963. (21) Acharya, A. K.; Chang, Y. A.; Jones, G. O.; Rice, J. E.; Hedrick, J. L.; Horn, H. W.; Waymouth, R. M. J. Phys. Chem. B 2014, 118, 6553− 6560. (22) Jeong, W.; Shin, E. J.; Culkin, D. A.; Hedrick, J. L.; Waymouth, R. M. J. Am. Chem. Soc. 2009, 131, 4884−4891. (23) Prasad, A. V.; Stubbs, L. P.; Ma, Z.; Zhu, Y. J. Appl. Polym. Sci. 2012, 123, 1568−1575. (24) Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37−40. (25) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109−2121. (26) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714−2720. (27) Maji, B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2011, 50, 6915−6919. (28) Maji, B.; Joannesse, C.; Nigst, T. A.; Smith, A. D.; Mayr, H. J. Org. Chem. 2011, 76, 5104−5112. (29) Semlyen, J. A. In Cyclic Polymers, 2nd ed.; Semlyen, J. A., Ed.; Kluwer: Dordrecht, 2000; p 790. (30) Reisch, J.; Iding, M.; Bassewitz, I. Monatsh. Chem. 1993, 124, 1225−1227. (31) Carafa, M.; Mesto, E.; Quaranta, E. Eur. J. Org. Chem. 2011, 2458−2465. (32) Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G. G.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2005, 127, 13798−13799. (33) Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Lundberg, P. N. P.; Dove, A. P.; Li, H.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Macromolecules 2006, 39, 7863−7871. (34) Lohmeijer, B. G. G.; Pratt, R. C.; Leibfarth, F.; Logan, J. W.; Long, D. A.; Dove, A. P.; Nederberg, F.; Choi, J.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Macromolecules 2006, 39, 8574− 8583.
1028
dx.doi.org/10.1021/mz500525n | ACS Macro Lett. 2014, 3, 1024−1028
